Lesions in the oral mucosa associated with the use of checkpoint inhibitors: A bibliometric and critical review.

AIMS: Immune-related adverse events (irAEs) linked to the use of immune checkpoint inhibitors (ICIs) have become increasingly frequent. To perform a bibliometric and critical review of the general panorama of publications on oral mucosal lesions (OML) associated with ICIs. METHODS AND RESULTS: Systematized searches were performed in four databases. The included studies were organized and bibliometric and clinical data were extracted and analyzed using VantagePoint and Microsoft Excel. Most of the 35 included studies were reports or case series (n = 33/94.2%). The American authors stood out (n = 17/48.5%), with the majority presenting only one publication. Independent groups carried out most of the publications (n = 31/88.5%). Over the years, publications have increased for users of nivolumab and pembrolizumab. In 21 studies (60%), OML were more common in men, between the 6th and 9th decades of life and who had lung carcinoma (n = 13/37.1%). Pembrolizumab (n = 17/48.5%) was the most used ICI. The patients were affected by one or more OML, including: ulcers (n = 28/80%) and erythema (n = 11/31.4%). Systemic corticosteroids (n = 24/68.5%) and the discontinuation of ICI use (n = 18/51.4%) were the main approaches used. CONCLUSION: OML related to the use of ICIs have become increasingly common. More accurate data need to be published.

Toxicidad sistémica y pulmonar por inmunoterapia: revisión narrativa a propósito de un caso / Systemic and pulmonary toxicity from immunotherapy: A narrative review and a clinical case report

En el último tiempo, la inmunoterapia se ha convertido en una opción terapéutica para diversos tipos de neoplasias, aumentando la sobrevida en muchos casos, pero también los efectos adversos asociados. Existen tres tipos de inmunoterapia utilizados en cáncer: Terapia de células T con receptor de antígeno quimérico (CAR-T), destacando como reacciones adversas el síndrome liberador de citoquinas (CRS) y el síndrome de neurotoxicidad (ICANS); Anticuerpos monoclonales (AcM), cuyos efectos adversos más comunes están relacionados con reacciones de hipersensibilidad; y los Inhibidores de puntos de control inmunitario (ICI) con toxicidad pulmonar claramente reportada. Para un correcto manejo de estas reacciones adversas se requiere un alto índice de sospecha, un adecuado diagnóstico diferencial y un tratamiento oportuno, basado principalmente en corticoides y guiado por criterios de gravedad. Se presenta el caso de un paciente con reacción granulomatosa sarcoidea posterior al uso de Nivolumab.

In recent times, immunotherapy has emerged as a therapeutic option for various neoplasms, significantly improving survival rates in many cases, albeit with associated adverse effects. There are three types of immunotherapy commonly used in cancer treatment: Chimeric Antigen Receptor T-cell Therapy (CAR-T), notable for adverse reactions such as Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS); Monoclonal Antibodies (mAbs), with the most common adverse effects being hypersensitivity reactions; and Immune Checkpoint Inhibitors (ICI), with well-documented pulmonary toxicity. Adequate management of these adverse reactions requires a high index of suspicion, accurate differential diagnosis, and timely treatment, primarily based on corticosteroids and guided by severity criteria. We present a case of a patient with granulomatous sarcoid-like reaction following the use of Nivolumab.

Autoimmune encephalitis related to nivolumab followed by tumor regression.

Immune checkpoints inhibitors have shown a remarkable improvement in overall survival of stage IV renal cell carcinoma patients. Nevertheless, there is a wide range of immune-related adverse events (IRAE) that arise from these revolutionary treatments. Autoimmune encephalitis is a rare but severe central nervous system IRAE in these cancer patients. The severities of these IRAEs preclude patients from continuing immunotherapy treatment. Few cases of autoimmune encephalitis with immunotherapy have been described in the literature and optimal clinical management of these events as well as patient's immune-mediated response after treatment suspension is still unclear. Here, we report a case of a 67 years-old woman with stage IV renal cell carcinoma under treatment with nivolumab who developed autoimmune encephalitis. After high doses of corticosteroids patient's condition improved significantly with full recovery after 5 days of treatment. Even though nivolumab was not reinstalled, a persistent response of her oncologic disease was evidenced. We expect that this case can contribute to the existing literature of both subjects, the management of autoimmune encephalitis as grade IV immune related adverse event and the responses of immune checkpoint inhibitors after IRAE.

Los inhibidores de puntos de control inmunológico han mostrado una importante mejoría en la supervivencia global de los pacientes con carcinoma de riñón estadio IV. Sin embargo, existe una amplia variedad de efectos adversos inmunomediados que surgen a partir de estos tratamientos revolucionarios. La encefalitis autoinmune es un infrecuente pero grave efecto adverso inmunomediado del sistema nervioso central en estos pacientes. La gravedad de este cuadro impide que los pacientes continúen con el tratamiento de inmunoterapia. Se han descrito pocos casos de encefalitis autoinmune con inmunoterapia en la literatura y aún no está claro el manejo clínico óptimo de estos eventos, ni cómo continua la respuesta inmunomediada después de la suspensión del tratamiento. Presentamos el caso de una mujer de 67 años con carcinoma de células renales estadio IV que desarrolló encefalitis autoinmune durante el tratamiento con nivolumab. La paciente mejoró significativamente luego del inicio del tratamiento con altas dosis de corticoides, con una recuperación completa después de 5 días del mismo. Si bien el nivolumab no se reinició, se evidenció una respuesta persistente de su enfermedad oncológica. Esperamos que este caso pueda contribuir a la literatura existente de ambos temas, el manejo de la encefalitis autoinmune como efecto adverso inmunomediado grado IV y las respuestas que se obtienen con la inmunoterapia luego de estos efectos adversos.

Real-world evidence of nivolumab for non-small-cell lung cancer in a developing country.

Nivolumab is a human programmed death receptor-1 blocking antibody, used as treatment option in patients with advanced non-small-cell lung cancer (NSCLC). We assessed the nivolumab efficacy in terms of survival and response to treatment as second-line (2L) or third-line (3L) therapy in patients with advanced NSCLC. This is a multicentric observational study. Data of patients with advanced NSCLC who received nivolumab as 2L or 3L treatment were analyzed retrospectively. Information regarding patient demographics and clinical backgrounds, treatment patterns from diagnosis to post-nivolumab treatment, effectiveness, and safety of nivolumab treatment were collected. The outcomes evaluated were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) to treatment. OS and PFS were estimated with the Kaplan-Meier method and the differences were evaluated through the log-rank test. Data of 178 patients were included. The median follow-up was 26.8 months (interquartile range (IQR): 20.3-40.4). Nivolumab was commonly used as a 2L treatment (77.5%). The outcomes in this setting (2L) were as follows: ORR was 21.0%, and the median PFS and OS were 5.5 months (95% confidence interval (CI): 4.5-6.5) and 12.4 months (95% CI: 10.8-14.0), respectively. In 3L, the ORR with nivolumab was 15.0%, the median PFS and OS were 4.1 months (95% CI: 3.1-5.1) and 10.1 months (95% CI: 9.4-10.6), respectively. Three patients (1.7%) required discontinuation due to toxicity. Nivolumab effectiveness and safety in this scenario was consistent with that reported by previous trials and other real-world data.

A phase 2 study of first-line nivolumab in patients with locally advanced or metastatic cutaneous squamous-cell carcinoma.

BACKGROUND: Cutaneous squamous-cell carcinoma (CSCC) is among the most frequent malignancies worldwide. For those not amenable to treatment with curative intent, immune checkpoint inhibition (ICI) with anti-programmed death receptor 1 (PD-1) antibodies has emerged as a novel therapeutic option. In this study, the authors sought to investigate the activity of the anti-PD-1 agent nivolumab in patients with advanced CSCC (aCSCC). METHODS: CA209-9JC was an open-label, single-arm, phase 2 study to evaluate the safety and/or efficacy of nivolumab in systemic treatment-naive patients with aCSCC. Nivolumab (3 mg/kg) was administered every 2 weeks until disease progression, unacceptable toxicity, or 12 months of treatment. The primary end point was the best objective response rate (BORR) as per RECIST 1.1 criteria. Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). RESULTS: Twenty-four patients with aCSCC were enrolled with a median age of 74 years (range, 48-93). Among the 24 patients evaluable for response, the BORR was 58.3% (14/24); there were no complete responses. With a median follow-up of 17.6 months, median duration of response has not been reached, and the estimated median PFS and OS were 12.7 and 20.7 months, respectively. Prior exposure to radiotherapy was associated with worse outcomes (p = .035, univariate analysis). Treatment-related adverse events of any grade and grade ≥ 3 occurred in 21 (87.5%) and six (25%) patients, respectively, and one patient discontinued nivolumab due to toxicities. CONCLUSIONS: Nivolumab resulted in robust antitumor activity, sustained responses, and good tolerability in systemic treatment-naive patients with aCSCC. These data provide further evidence to support the use of ICI as the standard treatment of aCSCC.

Severe oral ulcerative and lichenoid lesions associated with adrenal insufficiency in a patient treated with nivolumab: Report of a case and review of literature.

Nivolumab, an antibody against anti-programmed death type 1, has been used for treatment of advanced non-small cell lung cancer with improvement of overall survival. Usually, diarrhea, cutaneous rash, and pruritus are reported as the most common immune-related adverse effects of nivolumab therapy. Oral lesions and secondary adrenal insufficiency sometimes occur but usually are rare events. We report a case of a patient treated with nivolumab who then showed persistent oral ulcerative and lichenoid lesions, which were refractory to topical corticosteroids. The oral lesions were concomitant to nivolumab-induced adrenal insufficiency. These adverse events led to nivolumab discontinuation, which favored oral lesion healing and adrenal insufficiency remission. Through a brief review of the literature concerning nivolumab toxicity in the oral cavity, we discuss the clinical aspect and management of these lesions.

Prevalence of dermatological toxicities in patients with melanoma undergoing immunotherapy: Systematic review and meta-analysis.

BACKGROUND: Checkpoint inhibitors have revolutionized advanced melanoma care; however, their cutaneous side effects have not been definitively elucidated. OBJECTIVE: To identify the prevalence of cutaneous toxicity in patients with melanoma treated with immune checkpoint inhibitors as monotherapy and/or in combination with chemotherapy and/or radiotherapy. MATERIALS AND METHODS: We performed a systematic review and meta-analysis, which encompassed both clinical trials and observational studies describing the dermatological toxicities in patients treated with immune checkpoint inhibitors. The protocol was registered in the International Prospective Register of Systematic Review under the number CRD42018091915. The searches were performed using the CINAHL, Cochrane CENTRAL, LILACS, LIVIVO, PubMed, Scopus, and Web of Science databases. The methodological quality of the studies was evaluated with the JBI Critical Appraisal Checklist for Studies Reporting Prevalence Data. RESULTS: A total of 9,802 articles were identified in the databases. The final sample comprised 39 studies. The evaluated drugs were ipilimumab, tremelimumab, pembrolizumab, and nivolumab. The results suggest that the most prevalent side effect was grade 1 and 2 pruritus (24%), followed by grade 1 and 2 rash (21%) and grade 1 and 2 vitiligo (10%). CONCLUSION: The most prevalent side effects in patients treated with checkpoint inhibitors are pruritus, rash, and vitiligo, and they are rated mostly as grades 1 and 2 adverse events. Remarkably, vitiligo is most commonly found in patients treated with PD-1 inhibitors.

Systematic review and meta-analysis efficacy and safety of immune checkpoint inhibitors in advanced melanoma patients with anti-PD-1 progression: a systematic review and meta-analysis.

BACKGROUND: More than half of melanoma patients taking first-line anti-PD-1 therapy either express transient or no response at all. The efficacy and safety of secondary treatments for these patients are still not well established. Here, we evaluate the efficacy and safety of different melanoma FDA-approved ICI modalities used in post-anti-PD-1 refractory settings. MATERIALS AND METHODS: We searched the PubMed database and the ASCO meetings library for studies on advanced melanoma patients with cancer progression on anti-PD-1 therapy and were then treated with ipilimumab, nivolumab/ipilimumab combination, or retreated with anti-PD-1. Primary and secondary endpoints were efficacy and toxicity, respectively. Pooled estimates for each treatment group were obtained using a random or fixed effects model according to detected heterogeneity. RESULTS: Fourteen studies, of which 10 on ipilimumab, 2 on anti-PD-1 treatment, and 6 on combination therapies, were included, involving a total of 1460 patients. Twelve studies reported objective response rates (ORRs) and nine of them reported immune-related adverse events (irAEs). As for ORR, patients experienced a response that was inferior compared to the same therapy in treatment -naïve patients, with combination therapy having the best ORR of a pooled 23.08% (95% CI: 16.75% to 30.03%), followed by ipilimumab with a pooled ORR of 8.19% (95% CI: 5.78% to 10.92%). Survival data were also inferior in the ipilimumab cohort (mOS: 5.1 to 7.4 months) compared to ipilimumab in anti-PD-1 naive patients. As for grade 3/4 irAE occurrence, the ipilimumab cohort showed an estimate of 43.77% (95% CI 22.55% to 66.19%). CONCLUSION: Our findings provide the best current evidence that patients who progress on anti-PD-1 can still respond to different ICI modalities (ipilimumab with or without nivolumab, and retreatment or continuation beyond progression with anti-PD-1) with tolerable grade 3/4 irAEs. However, more prospective clinical trials are needed to confirm these results.

Five-Year Outcomes From the Randomized, Phase III Trials CheckMate 017 and 057: Nivolumab Versus Docetaxel in Previously Treated Non-Small-Cell Lung Cancer.

PURPOSE: Immunotherapy has revolutionized the treatment of advanced non-small-cell lung cancer (NSCLC). In two phase III trials (CheckMate 017 and CheckMate 057), nivolumab showed an improvement in overall survival (OS) and favorable safety versus docetaxel in patients with previously treated, advanced squamous and nonsquamous NSCLC, respectively. We report 5-year pooled efficacy and safety from these trials. METHODS: Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG PS ≤ 1, and progression during or after first-line platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg once every 2 weeks) or docetaxel (75 mg/m2 once every 3 weeks) until progression or unacceptable toxicity. The primary end point for both trials was OS; secondary end points included progression-free survival (PFS) and safety. Exploratory landmark analyses were investigated. RESULTS: After the minimum follow-up of 64.2 and 64.5 months for CheckMate 017 and 057, respectively, 50 nivolumab-treated patients and nine docetaxel-treated patients were alive. Five-year pooled OS rates were 13.4% versus 2.6%, respectively; 5-year PFS rates were 8.0% versus 0%, respectively. Nivolumab-treated patients without disease progression at 2 and 3 years had an 82.0% and 93.0% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression-free at 5 years, respectively. Treatment-related adverse events (TRAEs) were reported in 8 of 31 (25.8%) nivolumab-treated patients between 3-5 years of follow-up, seven of whom experienced new events; one (3.2%) TRAE was grade 3, and there were no grade 4 TRAEs. CONCLUSION: At 5 years, nivolumab continued to demonstrate a survival benefit versus docetaxel, exhibiting a five-fold increase in OS rate, with no new safety signals. These data represent the first report of 5-year outcomes from randomized phase III trials of a programmed death-1 inhibitor in previously treated, advanced NSCLC.

Nivolumab treatment beyond progressive disease in advanced non-small cell lung cancer.

PURPOSE: This study evaluated the efficacy and safety of nivolumab treatment beyond progressive disease (PD) in non-small cell lung cancer (NSCLC). PATIENTS/METHODS: Medical records of consecutive patients with advanced NSCLC who received nivolumab between December 2015 and December 2018 were reviewed. Clinical outcomes of three groups of eligible patients who received nivolumab as a second-line treatment after PD were compared based on Response Evaluation Criteria in Solid Tumors v1.1. We conducted subgroup analyses in patients with and without new lesions at first PD. RESULTS: Twenty-eight patients continued nivolumab treatment beyond PD (TBP). Post PD, 46 patients switched to other anti-cancer treatment (OAT), and 21 received no further anti-cancer treatment (NAT). There were no significant differences in overall survival (OS) or survival post progression (SPP) between TBP and OAT groups (OS: 15.6 vs. 13.4 months, P = .40, SPP: 12.2 vs. 9.3 months, P = .42). Subgroup analyses indicated that among patients without new lesions at first PD, SPP was longer in the TBP than in the OAT groups (12.6 vs. 9.3 months, P = .22, HR: 0.64; 95% CI 0.31‒1.31). The frequency of immune-related adverse events leading to discontinuation during nivolumab beyond PD was equivalent to that for pre-PD (10.7 vs. 12.6%). CONCLUSIONS: No significant benefits were associated with continuation of nivolumab for advanced NSCLC patients. Continuation of nivolumab beyond PD could be a more useful option in patients without new lesions at first PD. Treatment-related toxicities require attention during nivolumab treatment not only before PD but also beyond PD.

Eficacia y seguridad de cobimetinib más vemurafenib para el tratamiento de pacientes adultos con melanoma metastásico no resecable con progresión a nivolumab y quimioterapia con mutación BRAF V600E / Efficacy and safety of cobimetinib plus vemurafenib for the treatment of adult patients with unresectable metastatic melanoma with progression to nivolumab and chemotherapy with BRAF V600E mutation

INTRODUCCIÓN: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad del cobimetinib más vemurafenib, comparado con quimioterapia, para el tratamiento de pacientes adultos con melanoma metastásico no resecable con progresión a nivolumab y quimioterapia con mutación BRAF V600E. El melanoma es un tumor maligno que afecta a los melanocitos y es característicamente agresivo. La mayoría de los melanomas se localizan en la piel (95 %) y con menos frecuencia (5 %) en mucosas (oral, tubo digestivo, genital), retina o meninges. Alrededor de 50 % de los casos recién diagnosticados se presentan en pacientes de 35 a 65 años de edad. En el 2018, a nivel mundial se estimó que la tasa de incidencia estandarizada por edad fue de 3.1 casos por cada 100,000 habitantes en tanto que para el Perú la tasa de incidencia estandarizada por edad estimada fue de 2.7 casos por cada 100,000 habitantes, reportándose 321 casos nuevos en hombres y 317 casos nuevos en mujeres. Los estadios clínicos de la enfermedad describen cuatro etapas en el desarrollo de melanoma, siendo la última etapa, IV, que describe la presencia de metástasis a distancia "M1". La clasificación genómica, de acuerdo a las mutaciones más frecuentes definen cuatro grupos según la presencia o ausencia de mutaciones en los genes principales BRAF, RAS y NF1. Por su parte, la mutación BRAF es la más frecuentemente encontrada reportándose en cerca del 50 % de los melanomas cutáneos. El esquema de tratamiento empleado dependerá de la etapa en la que se encuentre el paciente al momento del diagnóstico según la clasificación clínica y genómica. El melanoma es un tumor maligno que afecta a los melanocitos y es característicamente agresivo. La mayoría de los melanomas se localizan en la piel (95 %) y con menos frecuencia (5 %) en mucosas (oral, tubo digestivo, genital), retina o meninges. Alrededor de 50 % de los casos recién diagnosticados se presentan en pacientes de 35 a 65 años de edad. En el 2018, a nivel mundial se estimó que la tasa de incidencia estandarizada por edad fue de 3.1 casos por cada 100,000 habitantes en tanto que para el Perú la tasa de incidencia estandarizada por edad estimada fue de 2.7 casos por cada 100,000 habitantes, reportándose 321 casos nuevos en hombres y 317 casos nuevos en mujeres. Los estadios clínicos de la enfermedad describen cuatro etapas en el desarrollo de melanoma, siendo la última etapa, IV, que describe la presencia de metástasis a distancia "M1". La clasificación genómica, de acuerdo a las mutaciones más frecuentes definen cuatro grupos según la presencia o ausencia de mutaciones en los genes principales BRAF, RAS y NF1. Por su parte, la mutación BRAF es la más frecuentemente encontrada reportándose en cerca del 50 % de los melanomas cutáneos. El esquema de tratamiento empleado dependerá de la etapa en la que se encuentre el paciente al momento del diagnóstico según la clasificación clínica y genómica. En el contexto de EsSalud, los pacientes diagnosticados con melanoma metastásico disponen de opciones terapéuticas como nivolumab o quimioterapia (dacarbazina, entre otros agentes citotóxicos). No obstante, en algunos pacientes, la neoplasia persiste y crece (a pesar de recibir el tratamiento correspondiente) y presentan además la mutación BRAF V600E, para los cuales no habría un tratamiento específico disponible más allá de la quimioterapia o mejor terapia de soporte. Es por ello, que los médicos especialistas de la institución sugieren el uso de cobimetinib más vemurafenib para el tratamiento dirigido a este tipo de mutación en pacientes con melanoma metastásico que progresan a quimioterapia y nivolumab. METODOLOGÍA: Se llevó a cabo una búsqueda sistemática de la literatura con el objetivo de identificar la mejor evidencia sobre eficacia y seguridad del cobimetinib más vemurafenib, comparado con quimioterapia, para el tratamiento de pacientes adultos con melanoma metastásico no resecable con progresión a nivolumab y quimioterapia con mutación BRAF V600E. Se utilizaron las bases de datos The Cochrane Library, PubMed, LILACS y el metabuscador TRIP Database. Priorizando evidencia proveniente de ensayos clínicos controlados aleatorizados (ECA). Se realizó una búsqueda manual dentro de las bases de datos pertenecientes a grupos que realizan evaluación de tecnologías sanitarias y guías de práctica clínica incluyendo la National Institute for Health and Care Excellence (NICE), Canadian Agency for Drugs and Technologies in Health (CADTH), Scottish Medicines Consortium (SMC), Institute for Clinical and Economic Review (ICER), The Institute for Quality and Efficiency in Healthcare (IQWiG por sus siglas en alemán), Base regional de informes de evaluación de tecnologías en salud de las Américas (BRISA) y páginas web de organizaciones especializadas en el manejo de melanoma. Se realizó una búsqueda adicional en la página web de clinicaltrial.gov para poder identificar ensayos clínicos en curso, corroborar los resultados y eventos adversos reportados en las publicaciones y de este modo disminuir el sesgo de publicación. La búsqueda sistemática se basó en una metodología escalonada, la cual consistió en la búsqueda inicial de estudios secundarios (del tipo revisiones sistemáticas de ensayos clínicos) que respondan a la pregunta PICO, seguido de la búsqueda de estudios primarios (del tipo ensayos clínicos aleatorizados). RESULTADOS: De acuerdo con la pregunta PICO, se llevó a cabo una búsqueda de evidencia científica relacionada al uso de cobimetinib más vemurafenib comparado con quimioterapia como tratamiento de pacientes adultos con melanoma metastásico no resecable con progresión a nivolumab y quimioterapia con mutación BRAF V600E. En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS, MA y ECA fase III). CONCLUSIONES: El presente dictamen preliminar tuvo como objetivo evaluar la evidencia disponible en relación a la eficacia y seguridad del cobimetinib más vemurafenib, comparado con quimioterapia, para el tratamiento de pacientes adultos con melanoma metastásico no resecable con progresión a nivolumab y quimioterapia con mutación BRAF V600E. Luego de la búsqueda sistemática de la literatura no se encontraron estudios de tipo ensayo clínicos aleatorizados, o revisiones sistemáticas que respondieran a la pregunta PICO de interés. Sin embargo, se identificaron tres GPC y tres ETS. La GPC de NCCN recomienda de manera explícita el uso de cobimetinib más vemurafenib para los pacientes con melanoma metastásico no resecable con mutación BRAF que progresaron a nivolumab. No obstante emplea evidencia que no corresponde con la población para dicha recomendación, debido a que el estudio de respaldo evalúa a pacientes que no han recibido tratamiento previo, es decir, lo utilizaron como primera línea de tratamiento. Por su parte, la guía de ESMO, si bien recomienda de manera general el uso de medicamentos anti-BRAF/MEK para pacientes que progresen a inmunoterapia, la bibliografía empleada para dicha recomendación no hace referencia al uso de cobimetinib más vemurafenib, sino a otros medicamentos. Por otro lado, la guía de SIGN no recomienda el uso de esta tecnología dentro de las opciones terapéuticas, no obstante, recomienda fuertemente la terapia paliativa para estos pacientes. En relación a la ETS de NICE, esta no recomendó el uso de cobimetinib más vemurafenib para nuestra población de interés, para ello utilizó evidencia procedente del estudio CoBRIM (resultados obtenidos de una población distinta y que se generalizaron para esta población) así como el análisis de costo efectividad que mostró que la intervención no era costo-efectiva para el sistema sanitario de Inglaterra. La ETS de CADTH, que correspondió a una revisión rápida para responder a una pregunta de investigación similar a la planteada en la pregunta PICO del presente dictamen, encontró solo tres estudios del tipo análisis retrospectivo, de baja calidad, que no brindaron información referente a uso de cobimetinib más vemurafenib, sino a otros inhibidores de BRAF. La ETS de pCODR, no recomienda el uso de cobimetinib más vemurafenib debido a que no existe evidencia suficiente que respalde el uso de esta tecnología en nuestra población de interés. En resumen, no se encontró evidencia que responda a la pregunta PICO para el presente dictamen, en ese sentido existe incertidumbre sobre el balance riesgo beneficio de cobimetinib más vemurafenib comparado con quimioterapia en la población de interés. En consecuencia, se necesitan estudios comparativos para poder determinar si el esquema cobimetinib más vemurafenib es más eficaz y seguro que la quimioterapia disponible actualmente en EsSalud. Por lo expuesto, el IETSI no aprueba el uso de cobimetinib más vemurafenib para el tratamiento de pacientes con melanoma metastásico no resecable con progresión a nivolumab y quimioterapia.

Immune-Related Adverse Events Involving Multiple Organ Sites in a Patient Treated With Nivolumab Plus Ipilimumab.

A 56-year-old white man with a 74 pack-year smoking history presented with macroscopic hematuria and a significant weight loss of 45 pounds in 6 months. His clinical laboratory tests indicated iron defi ciency anemia and a computed tomography (CT) scan showed a left kidney tumor, mediastinal lymph nodes, and multiple lung metastases. A percutaneous CT-guided kidney biopsy revealed grade 3 clear cell renal carcinoma based on World Health Organization/International Society of Urologic Pathology classifi cation. The patient started first line systemic treatment for intermediate-risk metastatic renal cell carcinoma (mRCC) with combination immunotherapy with nivolumab plus ipilimumab.1 After 10 days of the first cycle, he presented with a pruritic maculopapular rash covering 20% of his body surface.